Tumor Profiling Yields Insights Into Poor Osteosarcoma Response to Immunotherapy

By Marilynn Larkin

March 03, 2020

NEW YORK (Reuters Health) - Multiple genetic and cellular factors contribute to osteosarcoma's poor response to immunotherapy, researchers say.

"Despite its genomic complexity, treatment with immune checkpoint inhibitors has been ineffective for patients with osteosarcoma," Dr. Andrew Livingston of MD Anderson Cancer Center in Houston told Reuters Health by email. "This study gives insight into multiple ways in which osteosarcoma subverts the immune response, including limited neoantigen expression and an immunosuppressive tumor microenvironment."

"Chemotherapy combined with surgical resection remains the standard of care," he said. "Treatment with immune checkpoint inhibitors or other immunotherapeutic agents should be considered in the context of clinical trials as we seek to improve cure rates for teens and young adults with this rare disease."

As reported in Nature Communications, Dr. Livingston and colleagues studied osteosarcoma specimens from 48 children and adults (median age at diagnosis, 27; 60% male; 63% white) with relapsed (23%) and metastatic (51%) disease.

They performed whole genome, RNA, and T-cell receptor sequencing, as well as immunohistochemistry and reverse phase protein array profiling.

Unlike other cancer types, the genomic changes seen in the osteosarcomas were not associated with an increase in the expression of mutated proteins (neoantigens), which are thought to stimulate an immune response against the tumor.

Further, the median immune infiltrate level was lower than in tumor types where immune checkpoint inhibitors are effective - e.g., lung cancer, melanoma, and renal clear cell carcinoma - and T cell activity was low.

Gene expression analysis revealed "hot" tumors, which had high levels of immune infiltration, but also high levels of resistance pathways. "Cold" tumors had the lowest levels of immune infiltration, decreased expression of human leukocyte antigen, and a higher number of deleted genes, signaling higher genomic instability.

Notably, PARP2 expression levels were significantly negatively associated with the immune infiltrate.

The findings lay the groundwork for clinical trials that combine immune checkpoint inhibitors with other agents, such as PARP inhibitors or cell-based therapies, to improve outcomes, according to Dr. Livingston. "We currently have two clinical trials based upon this study that are in development, with plans to open at MD Anderson Cancer Center within the next year," he said.

Dr. Katherine Janeway, Senior Physician at Dana-Farber / Boston Children's Cancer and Blood Disorders Center and Director, Clinical Genomics, Dana-Farber Cancer Institute in Boston, commented in an email, "This is exactly the type of analysis required to reveal prognostic factors and identify avenues for new therapeutics."

"The patient population is small because osteosarcoma is a rare disease," she said. "Several efforts are underway, such as the just announced OSProject, which will facilitate sample collection to address this numbers problem." (http://bit.ly/2Ibc4Ln)

That project and others should also facilitate follow-up studies to validate the prognostic factors identified in the current study, she said.

SOURCE: https://go.nature.com/2TgHp5S Nature Communications, online February 21, 2020.

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